Açaí (Euterpe oleracea Mart.) in Health and Disease: A Critical Review

The açaí palm (Euterpe oleracea Mart.), a species belonging to the Arecaceae family, has been cultivated for thousands of years in tropical Central and South America as a multipurpose dietary plant. The recent introduction of açaí fruit and its nutritional and healing qualities to regions outside its origin has rapidly expanded global demand for açaí berry. The health-promoting and disease-preventing properties of this plant are attributed to numerous bioactive phenolic compounds present in the leaf, pulp, fruit, skin, and seeds. The purpose of this review is to present an up-to-date, comprehensive, and critical evaluation of the health benefits of açaí and its phytochemicals with a special focus on cellular and molecular mechanisms of action. In vitro and in vivo studies showed that açaí possesses antioxidant and anti-inflammatory properties and exerts cardioprotective, gastroprotective, hepatoprotective, neuroprotective, renoprotective, antilipidemic, antidiabetic, and antineoplastic activities. Moreover, clinical trials have suggested that açaí can protect against metabolic stress induced by oxidation, inflammation, vascular abnormalities, and physical exertion. Due to its medicinal properties and the absence of undesirable effects, açaí shows a promising future in health promotion and disease prevention, in addition to a vast economic potential in the food and cosmetic industries.


Introduction
The açaí palm (Euterpe oleracea Mart.), a species belonging to the palm tree (Arecaceae) family, is native to several countries in the Amazon region of tropical Central and South America, including Brazil, Ecuador, and Venezuela [1]. Although açaí has been cultivated in its indigenous terrain for thousands of years as a multipurpose dietary plant, its recent introduction to regions outside its origin has rapidly expanded global demand for its fruit (açaí or açaí berry) in particular [2]. To meet the increasing rates of açaí consumption, Brazil has become its most important producer and exporter [3].
On a yearly basis, Brazil generates over 9 billion US dollars in açaí-based revenue [4][5][6]. The popularized use of açaí has warranted further scientific research on its botanical background, remarkable nutritional profile, and bioactive properties. The seed of açaí constitutes 80% to 95% of the overall proportions of the fruit [7]. At maturity, an individual açaí berry is 1.5-2.0 cm wide with black and purple coloration [4]. Thus, substantial amounts of açaí are

Botanical Aspects
Açaí, popularly known as açaí-do-Pará, açaizeiro, or açaí-de-toceira, is a palm tree ( Figure 2a) native to the Amazon Basin [10]. Açaí palms have stems (Figure 2b) that can reach 30 m in height and 18 cm in diameter. These trees predominantly mature in a multistem pattern and can reach up to 45 stems in the adult stage of their development. At the base of each stipe, reddish, dense, superficial, and fasciculate roots with aerenchymas and lenticels create an aggregate network 30 to 40 cm above ground [27]. Açaí stems tend to be cylindrical, ringed, and erect. Scars from the senescent leaves ( Figure 2c) often form nodes and internodes along the açaí stem [28]. Additionally, the bunch-like inflorescences of açaí palms comprise both staminate and pistillate flowers [2,16]. Thus, açaí is a monoecious plant species. Açaí berries are spherical and organized into clusters formed by hundreds of individual fruits (Figure 2d). Each açaí berry has a diameter of 1.0 to 2.0 cm and an average mass of 1.5 g [27]. Externally, açaí fruit has a dark purple epicardium (Figure 2e). The maturity of açaí fruit is determined by its outermost color. At peak ripeness, the skin of açaí berries appears black [29]. Internally, the fruit contains a seed (Figure 2d) surrounded by an oleaginous pulp (mesocarp) that is 1.0 to 2.0 mm thick. Both the epicarp and mesocarp are edible and possess a flavor similar to that of a raspberry [27]. Although the açaí seed only weighs between 0.6 and 2.8 g and varies from 0.6 to 2.5 cm in diameter, it represents up to 85% of the volume of an individual açaí berry. Açaí seeds have a fibrous tegument, hard endocarp, and small embryo [2,15,27,29,30].

Botanical Aspects
Açaí, popularly known as açaí-do-Pará, açaizeiro, or açaí-de-toceira, is a palm tree ( Figure 2a) native to the Amazon Basin [10]. Açaí palms have stems (Figure 2b) that can reach 30 m in height and 18 cm in diameter. These trees predominantly mature in a multistem pattern and can reach up to 45 stems in the adult stage of their development. At the base of each stipe, reddish, dense, superficial, and fasciculate roots with aerenchymas and lenticels create an aggregate network 30 to 40 cm above ground [27]. Açaí stems tend to be cylindrical, ringed, and erect. Scars from the senescent leaves ( Figure 2c) often form nodes and internodes along the açaí stem [28]. Additionally, the bunch-like inflorescences of açaí palms comprise both staminate and pistillate flowers [2,16]. Thus, açaí is a monoecious plant species. Açaí berries are spherical and organized into clusters formed by hundreds of individual fruits (Figure 2d). Each açaí berry has a diameter of 1.0 to 2.0 cm and an average mass of 1.5 g [27]. Externally, açaí fruit has a dark purple epicardium (Figure 2e). The maturity of açaí fruit is determined by its outermost color. At peak ripeness, the skin of açaí berries appears black [29]. Internally, the fruit contains a seed (Figure 2d) surrounded by an oleaginous pulp (mesocarp) that is 1.0 to 2.0 mm thick. Both the epicarp and mesocarp are edible and possess a flavor similar to that of a raspberry [27]. Although the açaí seed only weighs between 0.6 and 2.8 g and varies from 0.6 to 2.5 cm in diameter, it represents up to 85% of the volume of an individual açaí berry. Açaí seeds have a fibrous tegument, hard endocarp, and small embryo [2,15,27,29,30].

Phytochemical Profiles
Notably, the disease-preventing effects of açaí are related to its composition of bioactive phytochemicals. The major constitutive phytochemicals of açaí are present throughout various parts of the plant.

Phytochemical Profiles
Notably, the disease-preventing effects of açaí are related to its composition of bioactive phytochemicals. The major constitutive phytochemicals of açaí are present throughout various parts of the plant.

Methodology for Literature Search and Included Studies
This review was designed on the basis of the following focal question: "What are the described health effects of açaí?" A literature search through PubMed, Cochrane, Embase, and Google Scholar databases was conducted to identify studies performed with açaí in relation to its health benefits, implications in disease, or both. Keywords directing the investigation included E. oleracea, açaí, phytochemicals, biological activity, in vitro and in vivo biological activities, pharmacological properties, and health benefits. Adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines was maintained throughout the process of data collection [43,44]. The literature search and selection process utilized in this study are depicted in Figure 7.

Methodology for Literature Search and Included Studies
This review was designed on the basis of the following focal question: "What are the described health effects of açaí?" A literature search through PubMed, Cochrane, Embase, and Google Scholar databases was conducted to identify studies performed with açaí in relation to its health benefits, implications in disease, or both. Keywords directing the investigation included E. oleracea, açaí, phytochemicals, biological activity, in vitro and in vivo biological activities, pharmacological properties, and health benefits. Adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines was maintained throughout the process of data collection [43,44]. The literature search and selection process utilized in this study are depicted in Figure 7. Eligible studies published from 2004 to 2022 were included in this review. Exclusion criteria were non-English language studies, unpublished data, poster presentations, and conference abstracts. For each clinical trial study, the detection, selection, and reporting of bias was utilized to carefully consider and evaluate risk of bias. Patient inclusion, intervention category, outcomes analyses, missing events, and data were also examined. Assessments of both bias and quality were performed in alignment with directives of the Cochrane Handbook for Systematic Reviews of Interventions [45]. The descriptive results of biases that were identified in the included in vivo animal studies followed Systemic Review Center for Laboratory Animal Experimentation (SYRCLE) guidelines [46]. We found 43 in vitro studies, 62 in vivo studies utilizing animal models, and ten clinical trials that aligned with our proposed focal question for this review. The patient populations involved in the clinical trials in this report are noteworthy. In the included studies, the distribution and distinction of patient populations are as follows: five with healthy subjects; one with patients with tinnitus; three with overweight individuals, one of which included patients diagnosed with metabolic syndrome (MetS); and one with patients with prostate cancer.

Preclinical Studies
Numerous preclinical studies have revealed the effects of açaí in vitro (Table 1) and in vivo (Table 2). A risk of bias assessment was performed for each animal study (Supplementary Table S1). The most relevant biological and pharmacological effects of açaí are described below. Eligible studies published from 2004 to 2022 were included in this review. Exclusion criteria were non-English language studies, unpublished data, poster presentations, and conference abstracts. For each clinical trial study, the detection, selection, and reporting of bias was utilized to carefully consider and evaluate risk of bias. Patient inclusion, intervention category, outcomes analyses, missing events, and data were also examined. Assessments of both bias and quality were performed in alignment with directives of the Cochrane Handbook for Systematic Reviews of Interventions [45]. The descriptive results of biases that were identified in the included in vivo animal studies followed Systemic Review Center for Laboratory Animal Experimentation (SYRCLE) guidelines [46]. We found 43 in vitro studies, 62 in vivo studies utilizing animal models, and ten clinical trials that aligned with our proposed focal question for this review. The patient populations involved in the clinical trials in this report are noteworthy. In the included studies, the distribution and distinction of patient populations are as follows: five with healthy subjects; one with patients with tinnitus; three with overweight individuals, one of which included patients diagnosed with metabolic syndrome (MetS); and one with patients with prostate cancer.

Preclinical Studies
Numerous preclinical studies have revealed the effects of açaí in vitro (Table 1) and in vivo (Table 2). A risk of bias assessment was performed for each animal study (Supplementary Table S1). The most relevant biological and pharmacological effects of açaí are described below. The blend protected erythrocytes from oxidative damage, prevented ROS production by polymorphonuclear cells, and reduced leukocyte migration through inhibition of FMLP [57]  Açaí suppressed the proliferation of rat C-6 brain glioma cells but did not affect human MDA-468 breast cancer cells [83]    The açaí seed extract did not diminish the cachectic syndrome in a rat model of tumorigenesis [92] Pasteurized açaí pulp with a high capacity for neutralizing free radicals The açaí pulp was purchased commercially and stored Female Fisher rats Diet supplemented with 2% of açaí pulp Oral by feeding Açaí pulp could effectively control the oxidative species production by neutrophils and increased liver antioxidant defenses [93] Anti-inflammatory Açaí oil The açaí oil was purchased commercially and stored Male Wistar albino rats and male Swiss albino rats Doses of 500, 1000, and 1500 mg/kg Orally The anti-inflammatory effects were associated with prostaglandin synthesis inhibition [19] Açaí stone extract The açaí berries were obtained, and the stone extract was made and stored Eight-week-old male mice 300 mg/kg/day Intragastric gavage The supplementation with açaí seed extract could significantly reduce inflammatory and oxidative responses [94] Analgesic Açaí stones extract rich in proanthocyanidins Hydroalcoholic extract Male Swiss mice The açaí stone extract was dissolved in distilled water at a concentration of 10 mg/mL

Intragastric gavage
The extract exerted antinociceptive effects [95]     The extract, in conjunction with exercise training, decreased glucose and lipid serum levels, serum hepatic enzymes, and liver triglycerides [113] Filtered açaí pulp with 458.6 mg GAE/100 g of polyphenols and 13.59 mg/100 g of monomeric anthocyanins The açaí oil was purchased commercially and stored Female Fischer rats 2 g/day Intragastric gavage The açaí supplementation protected liver steatosis and injuries in a high-fat diet-rats [114] Açaí water extract The açaí pulp was obtained commercially and stored for future aqueous extract preparation Male Swiss mice 3 g/kg/day Intragastric gavage The extract prevented liver damage, attenuated inflammation, and decreased oxidative stress [115] Açaí water extract with 118.13 mg GAE/100 g of phenolic compounds and 9.23 mg/100 g of flavonoid compounds The açaí pulp was obtained commercially and stored for future aqueous extract preparation Male Swiss mice 3 g/kg/day Intragastric gavage The use of açaí increased the production and effectiveness of adiponectin, improving insulin sensitivity and increasing PPAR-α-mediated fatty acid oxidation [116]      The extract significantly suppressed the establishment and growth of endometriosis [139] Dried açaí Açaí-enriched diet Male Wistar rats The dried açaí was mixed with the standard diet but was not calculated Oral by feeding The açaí-supplemented diet exerted eye protection and antioxidant effects [140] Açaí extract Not reported C57BL/6NCrSlc mice 10 mL/kg/day Intragastric gavage The use of açaí can stimulate erythropoietin production by inducing a hypoxic renal condition [141] Abbreviations

Antioxidant Activity
Among the health implications of açaí included in this discussion, antioxidant and anti-inflammatory faculties have been documented most frequently in the current literature. A large quantity of in vitro evidence exists in support of the antioxidant capacity of several compounds (e.g., polyphenols, flavonoids, anthocyanins) present in açaí [41,42,142,143]. Brunschwig et al. [42] evaluated the in vitro antioxidant effect of açaí root and leaflet extracts using ferric reducing antioxidant power (FRAP), oxygen radical absorption capacity (ORAC), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) tests. In this study, both açaí root and leaflet extracts were found to exhibit powerful antioxidant activity against superoxide anion radical and promote the inhibition of liposome, hydroxyl radical, peroxyl radical, and DPPH radical oxidation. Evidence suggests that these effects were induced by hydroxycinnamic acids and ACGs present in açaí root and leaflet, respectively [27,144]. In a study evaluating the antioxidant capacity of several commercial samples of powdered açaí pulp, Carvalho et al. [39] demonstrated that all brands of açaí pulp presented activity in ORAC and 2,2azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays. The authors reported data supportive of antioxidant effects correlated to the presence of phenolic compounds in açaí.
In a similar manner, Earing et al. [145] evaluated the composition and antioxidant capacity of açaí food supplements in several different formulations (e.g., capsule, powder, frozen pulp, liquid) according to chemical profiles and antioxidant properties. Notably, over half of the açaí supplements were found to either consist of little to no açaí berry or enough water to significantly dilute the chemical constituents of the fruit. Moreover, few supplements contained unlisted ingredients that altered the chemical properties of the açaí products. Nonetheless, a strong positive correlation (r = 0.978) was identified between antioxidant capacity and total phenol content. Further, Costa et al. [75] evaluated the phytochemical profile of hydroethanolic açaí extract from a commercial dietary açaí powder supplement and investigated the in vitro influence of açaí phytochemicals on angiogenesis and oxidative biomarkers in human microvascular endothelial cells (HMEC-1). Analysis of the hydroethanolic açaí extract revealed the presence of considerable quantities of anthocyanins, primarily cyanidin-3-O-rutinoside, and various flavonoids with promising health implications [75]. HMEC-1 treated with hydroethanolic açaí extract demonstrated decreased reactive oxygen species (ROS) production, upregulated antioxidant activity of catalase (CAT) and superoxide dismutase (SOD), and increased antiangiogenic activity without cytotoxicity [75]. Figure 8 summarizes the antioxidant effects of açaí.

Anti-Inflammatory Activity
Injury, toxins, infection, genetic defects, and trauma can induce resident immune cell activation [4]. Subsequent signaling and secretion of chemokines and cytokines, such as cyclooxygenase 2 (COX-2), tumor necrosis factor-α (TNF-α), and nuclear factor-κβ (NF-κβ), recruit immune cells to the affected region and cause inflammatory infiltration [54,56,146,147]. Historically, in vitro models have been used to evaluate the anti-inflammatory effects of açaí. Dias et al. [147] utilized noncytotoxic concentrations of açaí extract in human colon myofibroblast CCD-18Co cells to investigate the inflammatory protein expression, ROS suppression, and anti-inflammatory activity of açaí phenolic compounds. Açaí extract was noted to decrease COX-2, TNF-α, and NF-κβ expression induced by lipopolysaccharide (LPS) in human colon myofibroblasts. Because the downregulation of biomarkers, such as COX-2, TNF-α, and NF-κβ, is vital to the reduction of inflammation, these results provide further evidence of anti-inflammatory activities of phenolic compounds in açaí. Another in vitro study performed by Machado et al. [148] demonstrated that hydroalcoholic extract of açaí pulp and bark prevented the increase of proinflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), TNF-α, and interferon-γ (IFN-γ), as well as ROS and nitric oxide (NO), on an inflammatory macrophage model. In this study, açaí was also shown to promote the increase of anti-inflammatory interleukin 10 (IL-10) levels. Thus, data suggests the capacity of açaí as an agent of inflammatory regulation and inhibition [56,57,148]. Figure 9 shows the potential anti-inflammatory actions of açaí.
In this study, açaí was also shown to promote the increase of anti-inflammatory interleukin 10 (IL-10) levels. Thus, data suggests the capacity of açaí as an agent of inflammatory regulation and inhibition [56,57,148]. Figure 9 shows the potential anti-inflammatory actions of açaí.

Antinociceptive and Analgesic Activity
Pain can have a negative impact on quality of life, as well as the performance of daily activities. Currently, nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are common pharmacological options of the treatment of pain. The anti-inflammatory, antihypertensive, antioxidant, and vasodilatory activities of açaí has resulted in the exploration of its value as an antinociceptive and analgesic agent [56,95,97,118,149]. According to Sudo et al. [95], the use of açaí seed extract reduced nociceptive responses to acute/inflammatory pain, including acetic acid-induced writhing, thermal hyperalgesia, and carrageenan-induced thermal hyperalgesia in mice. The antinociceptive responses to açaí were dose-dependent. Furthermore, açaí extract diminished the neurogenic and inflammatory phases resulting from intraplantar injections of formalin and prevented chronic pain, including mechanical allodynia and thermal hyperalgesia, induced by spinal nerve ligation. Açaí displayed noteworthy antinociceptive action through multiple pathways and, therefore, may be considered in the production of new analgesic therapeutics. Additionally, Marinho et al. [150] showed that extracts from açaí flowers and spikes have antinociceptive activity in rat models. The flower extract has significant peripheral activity, reducing the total number of abdominal contortions by up to 50% in an acetic acid-induced abdominal writhing pain model. Although none of the açaí extracts were able to change the analgesia indices in a hot plate pain model, higher dosages of açaí achieved positive spinal antinociceptive effects. Açaí may have potential as therapeutic in the treatment and management of pain.

Antimicrobial Activity
Due to growing antimicrobial resistance, the pharmaceutical field is constantly seeking new alternatives to oppose relevant pathogens. The high polyphenol content of açaí has been associated with antimicrobial activity [60]. One study has investigated the effects of açaí oil (EOO) complex against Escherichia coli, Pseudomonas aeruginosa, Streptomyces aureus, and Enterococcus faecalis [151]. EOO complexes containing β-cyclodextrin (β-CD) or hydroxypropyl-β-cyclodextrin (HP-β-CD) were also investigated. Results showed a modulatory antibacterial response of EOO, EOO-β-CD, and EOO-HP-β-CD and revealed that EOO can successfully form inclusion complexes, especially with β-CD. Minimum inhibitory concentration (MIC) demonstrated that the inclusion complexes in EOO-β-CD and EOO-HP-β-CD exhibited antibacterial effects against Gram-positive and Gramnegative strains and were considerably more potent than pure EOO. Moreover, EOO and most of its complexes exhibited a synergistic effect with ampicillin against E. coli [21]. Overall, data elucidating the antimicrobial response elicited through these complexes carries is of great importance to the pharmaceutical industry, as açaí may be considered in the development of new forms of microbicidal drugs.
Dias-Souza et al. [62] studied the antimicrobial effects of methanolic extract of açaí pulp against S. aureus and found it to be effective against planktonic cells and biofilms of this microorganism. Furthermore, hydroalcoholic extracts produced from dried pulp, leaves, and seeds of açaí demonstrated significant antimicrobial activity against Clostridium perfringens, S. aureus, and P. aeruginosa [63]. Hence, these studies suggest that the use of açaí extract in formulations of phytotherapeutic substances may be a sustainable option for antimicrobial treatment. Further, Silva et al. [24] evaluated the activity of açaí juice on Leishmania amazonensis and Leishmania infantum and found a reduction in the number of promastigotes, augmented synthesis of ROS, and the induction of cell death phenotypes in both species. The use of açaí juice for 72 h not only engendered protective effects against L. amastigotes and strongly diminished IL-17 levels, but also reduced the number of intracellular amastigotes in macrophages infected with L. amastigotes and L. infantum [24]. Of note, the authors did not observe cytotoxic effects in murine macrophages treated with açaí juice. Murine macrophages often serve as the initial screening tool for bioactivities of natural products on in vivo or human primary cells. Accordingly, these results revealed the leishmanicidal activity of açaí juice against species responsible for the onset of cutaneous and American visceral leishmaniasis without concomitant cytotoxic consequences for the host cell.

Antiulcer Activity
Gastric ulcers are one of the most common conditions afflicting humans. Current treatments for gastric ulcers include H2-receptor antagonists, M1-receptor blockers, and proton pump inhibitors. However, these drugs can be costly, have health-associated side effects, and result in relapse. For this reason, more efficacious and inexpensive therapeutics for gastric ulcers are in high demand. Cury et al. [96] investigated the in vivo effects of dried açaí fruit extract (DAE) on ethanol-induced gastric ulcers through animal models and noted gastroprotective activity. In this study, 30 to 100 mg/kg doses of DAE resulted in a 48-83% reduction of ulcerated area. Furthermore, DAE demonstrated in vitro radical scavenger capacity through increased levels of glutathione, normalized levels of SOD, increased CAT activity, and reduced levels of TNF-α levels in comparison to the control group. In sum, these findings indicate that açaí extract may both decrease inflammation and facilitate the maintenance of oxidative balance in gastric mucosa. Thus, açaí is a promising natural option for pharmacotherapy aiming to protect the gastric mucosa.

Neuroprotective Activity
There are limited investigations examining the impact of açaí berry on cognitive function or brain health. The experiments available have established that açaí largely confers its neuroprotection through antioxidant and anti-inflammatory mechanisms, restoration of mitochondrial function, and inhibition of toxic protein aggregation [152][153][154][155]. Antioxidants have a clear role in the neutralization of free radicals and, therefore, the protection of cells against oxidative damage caused by free radicals [14]. Oxidative damage has been linked to the development of chronic illnesses and is the common cytopathology of many neurodegenerative diseases (NDDs) [156,157]. Neuronal degradation and the development of NDDs are generally multifactorial processes incited by a genetics, aging, and environmental factors linked to the progression of oxidative stress, chronic neuroinflammation, mitochondrial dysfunction, anomalous protein accumulation in brain tissues, and excitotoxicity [72,148,155]. Data have shown that neurons unequipped for adequate response to oxidative stress undergo apoptotic or necrotic death [69]. Thus, oxidative stress is a primary mechanism responsible for neuronal degradation. In comparison to other organs, the relative lack of antioxidant enzymes, abundance of readily oxidizable substances, and substantial oxygen requirements in the brain render it more susceptible to free radical damage [72]. Hence, materials rich in antioxidants can afford neuroprotective effects against oxidative damage [156].
The anti-inflammatory potential of açaí extract was evaluated via an in vitro microglial model that substantiated its modulation of nucleotide oligomerization domain (NOD)-like receptor pyrin domain-containing 3 (NLRP3) inflammasome proteins and antioxidant pathways, augmentation of anti-inflammatory cytokines, and reduction of pro-inflammatory cytokines [155]. Microglia were exposed to LPS and nigericin, inducers of inflammation, then treated with açaí. Results confirmed the efficaciousness of açaí in neuroinflammatory prophylaxis and, therefore, the potential of the fruit in the prevention and treatment of neuropsychiatric diseases associated with neuroinflammation. De Souza et al. [157] also validated that açaí attenuated stress-induced inflammatory and oxidative signals in BV-2 microglial cells insulted with LPS. This study evaluated the success of açaí as an anti-neuroinflammatory agent. Similarly, freeze-dried hydroalcoholic açaí berry extract was found to reduce cellular proliferation, release of ROS, proinflammatory cytokines, and caspase-1 protein expression [66]. Furthermore, açaí berry extract exhibited the capacity to induce cell cycle arrest, suggesting the role of açaí as an inhibitor and regulator of the inflammatory response. Another study, investigating the antioxidant and neuroprotective actions of hydroethanolic extracts from six açaí genotypes, illustrated the potent scavenging capability of açaí via ABTS, deoxyribose, and glutathione oxidation assays, as well as human neuroblastoma SH-SY5Y cell lines subjected to hydrogen peroxide (H 2 O 2 ). Analysis of ABTS and deoxyribose assays revealed no differences in antioxidant activity amongst the various açaí genotypes. All hydroethanolic extracts were found to reduce ROS produced by H 2 O 2 in SH-SY5Y cells, elucidating their neuroprotective effects [67].
The vulnerability of the brain to oxidative stress, in addition to its energy requirements for neurotransmission, greatly increases the risk of mitochondrial dysfunction in neural tissue [69]. Data supports the correlation between mitochondrial dysfunction and neuronal death in NDDs [155]. Additionally, the current literature has linked the pathophysiology and cellular modifications of neuropsychiatric illnesses, such as bipolar disorder (BD) and schizophrenia (SCZ), to mitochondrial dysfunction and oxidative stress, respectively [67]. Machado et al. [67] examined the in vitro role of açaí in modulation of mitochondrial function and oxidative metabolism. In this study, freeze-dried hydroalcoholic açaí extract reversed mitochondrial dysfunction incited by rotenone treatment in human neuroblastoma SH-SY5Y cells. Açaí extract not only augmented protein amount and enzyme activity of mitochondrial complex I, but also to reduced cellular ROS and lipid peroxidation [67,72]. Mitochondrial complex I is the first enzyme of the electron transport chain (ETC), a series of protein complexes responsible for oxidative phosphorylation in mitochondria. Restoration of mitochondrial function was primarily achieved through overexpression of NDUFS7 and NDUFS8 nuclear mitochondrial complex I subunit genes and improvement of their proteomic expression [67]. Collectively, these results led the authors to suggest that the neuropharmacological faculty of açaí may warrant its candidacy in the development of drugs used to treat BD, SCZ, and other neuropsychiatric diseases.
Neurodegeneration in the setting of NDDs can cause significantly altered neuron viability. This can lead to the overproduction, inadequate clearance, and ultimately, aggregation of toxic proteins in or around brain tissue [69]. The death of neurons is precipitated by toxic protein accumulation often caused by dysfunctional autophagy [69]. Therefore, normal cellular autophagy is a crucial determinant of neuron viability protein homeostasis in the brain. Wong et al. [70] showed that açaí berry extract significantly improved neuronal cell viability after exposure to beta-amyloid (Aβ), specifically Aβ1-42. In comparison to pure phenolics, the phenolic compounds of açaí extract exhibited more potent effects on Aβ1-42 fibril inhibition and morphological modification. Toxic protein misfolding and accumulation are pathological hallmarks of many NDDs [69]. The ability of açaí extract to efficaciously impede Aβ1-42 aggregation reinforced existing evidence of the neuroprotective effect of this fruit. Furthermore, it can be seen that the molecular mechanisms of açaí berry may contribute to the improvement of protein homeostasis in the brain [69].
Brain injury from seizures can result in neuronal cell death [65]. Factors contributing to seizure-induced neuronal cell death include oxidative stress, mitochondrial dysfunction, altered levels of cytokines, and genetics. Based on this association, Souza et al. [23] examined the possible anticonvulsant and neuroprotective activities of commercial clarified açaí juice and showed that the juice did not modify spontaneous locomotor activity in mice. In this study, four doses (10 µL/g) of the juice provided adequate anticonvulsant activity to augment latencies to both first myoclonic jerk and first generalized tonic-clonic seizure. The administration of açaí significantly reduced the total duration of tonic-clonic seizures induced by pentylenetetrazol. Moreover, açaí juice prevented electrocortical modification, as well as lipid peroxidation, caused by the use of pentylenetetrazol in the cerebral cortex [23]. Importantly, this is the first data to demonstrate the neuroprotective effects of açaí against seizures and seizure-related oxidative stress.
Many neurodegenerative diseases eventually lead to symptoms of depression. Because depression has been linked to oxidative stress, the antidepressant effects of açaí berry have also been explored [156]. Açaí juice has been shown to exhibit antidepressant actions similar to those of imipramine, which inhibits neuronal reuptake of norepinephrine and serotonin neurotransmitters. Currently, the similitude between these two substances and their antiaging and antidepressant effects is thought to be due to their roles in the prevention of lipid peroxidation and increase of telomerase reverse transcriptase mRNA expression [72,[156][157][158]. Specifically, açaí juice provides protection against neuronal loss related to the depressive-like state and increased nitrite levels in hippocampal cells [104]. Additionally, the reduction of oxidative damage in the brain as a result of açaí treatment may be a productive intervention of the aging process [84]. Sun et al. [156] investigated the effects of açaí pulp supplementation in Drosophila melanogaster fed a high-fat diet. This study found that açaí supplementation increased the transcription of genes related to a small heat-shock-related protein and two detoxification genes. Açaí also reduced transcription of phosphoenolpyruvate carboxykinase (PEPCK), a critical gene in the appropriate regulation of gluconeogenesis. Moreover, açaí increased the lifespan of females subjected to oxidative stress, suggesting that açaí improves survival [159]. Açaí may be an effective antagonist of the deleterious effects of high-fat diets and oxidative stress, which accelerate the aging process [87,[115][116][117]158,159].

Antilipidemic Activity
Dyslipidemia is precipitated by disruptions in lipid metabolism that result in chronically elevated serum lipids and, therefore, increased predisposition to CVDs, obesity, atherogenic processes, diabetes, and metabolic syndrome (MetS) [106,160]. Dietary unsaturated fats can reduce the risk of CVD. Several studies have shown that the consumption of açaí oil and its rich content of unsaturated fatty acids may benefit lipid profiles [18]. Liz et al. [159] investigated the effects of the daily consumption of 200 mL of açaí juice in adults and discovered increased levels of high-density lipoprotein cholesterol (HDL) in comparison to baseline levels. Moreover, Bem et al. [113] demonstrated that açaí seed extract, in conjunction with exercise training, reduced total cholesterol levels by 81.2% in diabetic rats. In addition, Faria et al. [105] examined the actions of açaí oil on hyperlipidemia induced by Cocos nucifera L. saturated fat in rats. Although no alterations in triglycerides were noted, there were reductions in total cholesterol and low-density lipoprotein cholesterol (LDL). A treatment regimen of both açaí oil and simvastatin, a common anticholesterolemic drug, also prevented the formation of atheromatous plaques in the vascular endothelium of rats [106,109]. Comparably, a study performed by Souza et al. [106] evaluated the effects of açaí oil in Triton-induced dyslipidemia in rats. The results showed that animals treated with açaí oil and simvastatin exhibited significantly reduced total cholesterol, LDL, and triglyceride levels, as well as increased HDL levels. Thus, the authors concluded that açaí oil is antihypertriglyceridemic, anticholesterolemic, and advantageous in the treatment of dyslipidemia [107]. For this reason, açaí oil may also have potential as a preventive agent for CVDs [20,120].
Souza et al. [107] proposed that the antilipidemic effects promoted by açaí primarily occur via increased expression of genes involved in cholesterol secretion and biosynthesis, including ATP-binding cassette, subfamily G transporters (ABCG5 and ABCG8), and LDL receptor (LDL-R) genes. This study evaluated the effects of açaí pulp in rats with dietinduced hypercholesterolemia. The experimental group fed a standard diet supplemented with açaí displayed a significant reduction in total cholesterol and LDL levels and an increase in HDL levels. Additionally, there was an increase in fecal cholesterol excretion and enhanced expression of the LDL-R, 7α-hydroxylase, subfamily G transporters, and ATPbinding cassette genes in the rats [115]. These findings suggest that the consumption of açaí pulp positively effects diet-induced hypercholesterolemia by augmenting the expression of ATP-binding cassette, subfamily G transporters, and LDL-R genes [115,[160][161][162].

Hepatoprotective Activity
Globally, the most prevalent liver condition is nonalcoholic fatty liver disease (NAFLD) [111]. NAFLD is an umbrella term for a variety of progressive illnesses, including steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. Despite the multifactorial onset and progression of NAFLD, specific intracellular contributory factors, such as inflammation, oxidative stress, mitochondrial dysfunction, altered endoplasmic reticulum (ER) homeostasis, and apoptosis, have been identified [115]. Therefore, the phenolic compounds of açaí are regarded as prospective therapeutic agents in the treatment of NAFLD due to their high antioxidant and anti-inflammatory capacities [47,163,164,165]. Freitas et al. [115] tested the actions of an aqueous açaí extract in HepG2 cells and its effects on inflammation, oxidative stress, and ER stress. These activities were also tested in a murine model of diet-induced NAFLD. Notably, açaí exhibited potent in vitro antioxidant capacity. In vivo açaí extract administration (3 g/kg) attenuated liver damage, as

Hepatoprotective Activity
Globally, the most prevalent liver condition is nonalcoholic fatty liver disease (NAFLD) [111]. NAFLD is an umbrella term for a variety of progressive illnesses, including steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. Despite the multifactorial onset and progression of NAFLD, specific intracellular contributory factors, such as inflammation, oxidative stress, mitochondrial dysfunction, altered endoplasmic reticulum (ER) homeostasis, and apoptosis, have been identified [115]. Therefore, the phenolic compounds of açaí are regarded as prospective therapeutic agents in the treatment of NAFLD due to their high antioxidant and anti-inflammatory capacities [47,[163][164][165]. Freitas et al. [115] tested the actions of an aqueous açaí extract in HepG2 cells and its effects on inflammation, oxidative stress, and ER stress. These activities were also tested in a murine model of diet-induced NAFLD. Notably, açaí exhibited potent in vitro antioxidant capacity. In vivo açaí extract administration (3 g/kg) attenuated liver damage, as evidenced by decreased levels of alanine aminotransferase (ALT) and serum TNF-α, a reduced number of inflammatory cells, and decreased lipid peroxidation and carbonylation of proteins [163]. Fundamentally, the results of this study propound the idea that açaí extract may have hepatoprotective activity and, thus, the capacity to prevent the progression of liver damage associated with NAFLD [111,115,163]. Additionally, Song et al. [163] evaluated the properties of an anthocyanin-rich extract of açaí fruit in male SPF C57BL/6J mice fed a low-fat diet, high-fat diet, or high-fat diet supplemented with açaí extract for fourteen weeks. Consequently, it was demonstrated that animals treated with açaí presented less hepatic steatosis, obesity, and insulin resistance [35,110,112]. Further, Barbosa et al. [110] showed that the use of pasteurized frozen açaí pulp in female rats fed a high-fat diet two weeks before mating, as well as during gestation and lactation, could improve liver steatosis and reduce liver weight, serum cholesterol, and hepatic fat content. In the offspring, the high-fat diet supplemented with açaí also reduced liver weight and serum cholesterol, suggesting that açaí supplementation may attenuate NAFLD and protect offspring from the detrimental effects of excess lipids in the setting of a high-fat maternal diet [108].
Another study revealed that the use of açaí seed flour could prevent obesity-induced hepatic steatosis in mice [108]. In this study, dietary incorporation of 15% or 30% açaí seed flour led to improved lipid profiles and protective effects against weight gain. The açaí-supplemented diet also reduced lipogenesis, which contributed to the inhibition of NAFLD development. Moreover, açaí consumption was found to influence the modulation of proteins involved in cholesterol excretion and production [35,112]. Increased fecal excretion of bile acids and cholesterol was observed in the setting of a diet supplemented with açaí. Comprehensively, this study evinces the use of açaí seed flour as a tool for the prevention of obesity development and its complications, especially hepatic steatosis. In addition, a study performed by Bem et al. [113] evaluated the use of açaí seed extract and exercise training on hepatic steatosis in diabetic rats and discovered that the açaí treatment, in combination with exercise, could reduce total cholesterol (81.2%), aspartate aminotransferase (AST) (51.7%), hepatic triglycerides, (66.8%), and steatosis (72%) compared to a sedentary control group. Açaí supplementation, in conjunction with exercise training, decreased the expression of hepatic lipogenic proteins and augmented both antioxidant defense and cholesterol transporters in animals with type 2 diabetes mellitus (T2DM). Thus, açaí treatment, combined with exercise, may provide protection against both hepatic steatosis and oxidative stress [105,117,118,138].
The effects of filtered açaí pulp on the expression of paraoxonase (PON) activity in rats with NAFLD have also been investigated [166,167]. Rats fed a high-fat diet supplemented with açaí displayed increased hepatic and serum PON-1 activity, decreased LDL oxidation, and upregulated expression of PON1 and APOA1, which encodes apolipoprotein A-I (ApoA-I), in the liver. Overall, the consumption of açaí pulp reduced liver damage, fat infiltration, and triglyceride content, suggesting its potential efficacy against hepatic steatosis and liver injuries [114]. A study conducted by Oliveira et al. [35] also indicated açaí as a therapeutic agent in the prevention of liver steatosis. In this report, the use of açaí seed extract reduced cholesterol accumulation and triglycerides in the liver and, therefore, reduced hepatic steatosis. The increased expression of lipogenic proteins such as sterol regulatory element binding protein-1c (SREBP-1c) and hydroxymethylglutaryl-coenzyme A reductase (HMG-CoA reductase), as well as the decreased the expression of phosphorylated 5 adenosine monophosphate-activated protein kinase (p-AMPK), were antagonized by açaí seed extract. In addition, açaí increased the expression of cholesterol excretion transporters [35,115]. The antioxidant effect of açaí seed extract in the liver was illustrated by the restoration of SOD, CAT, and glutathione peroxidase (GPx) activities [35,114]. These findings reinforce the prospective use of açaí as a method to amplify defense mechanisms against oxidative stress through dietary antioxidants.
Alcoholic liver disease (ALD) is the most prevalent cause of advanced liver disease and has been linked to high levels of global mortality and morphological consequences, includ-ing alcoholic hepatitis, steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma [114]. The result of excessive ethanol metabolism in the setting of chronic alcohol abuse is substantial ROS and acetaldehyde production. Because metabolite-induced inflammatory factors and oxidative stress are implicated in the progression of ALD, antioxidants capable of reducing ethanol-induced oxidative stress may be considered as preventive agents [114]. Zhou et al. [112] observed that the use of açaí puree in alcohol-treated Wistar rats significantly decreased hepatic enzymes (alkaline phosphatase (ALP), ALT, and ASP), triglycerides, cholesterol, and hepatic index. Moreover, açaí intake attenuated alcohol-induced oxidative stress, as marked by the reduction of malondialdehyde and triglycerides, higher SOD activity, and increased levels of glutathione. There was also a reduction in the hepatic expression levels of inflammatory mediators stimulated by ethanol metabolic processes, such as IL-8, TNF-α, NF-κB, TGF-β, and CD-68. Additionally, treatment with açaí attenuated histopathological liver damage, including severe steatosis and inflammatory cell infiltration [114]. The anti-inflammatory and antioxidative activities of açaí may warrant its application in the treatment of ALD.

Antidiabetic Activity
Worldwide, T2DM is a serious public health crisis reaching epidemic proportions [117]. Diabetes is a major cause of kidney failure, cardiovascular events, blindness, and lower limb amputation. T2DM is associated with an increased risk of morphological and metabolic modifications in vital organs such as the liver [105]. In a study conducted with obese mice on a high-fat diet, Silva et al. [108] revealed that the incorporation of 15% or 30% dietary açaí seed flour procured beneficial effects against insulin resistance. Furthermore, after 12 weeks of açaí intake, the animals presented lower serum glucose, insulin, and leptin concentrations. The reduction of lipogenesis induced by açaí seed flour consumption also prevented the development of hypertrophic obesity [112]. Bem et al. [113] demonstrated that the use of the açaí seed extract and exercise training in diabetic rats can reduce blood glucose by 70.2%. Oliveira et al. [35] examined the impact of açaí seed extract on adiposity and hepatic steatosis and showed its potential to reduce glucose levels in mice treated with a high-fat diet. Hence, açaí has protective activities against obesity and its comorbidities, including insulin resistance and elevated glucose levels. Figure 10 shows the antidiabetic and antilipidemic effects of açaí.

Antihypertensive Activity
Cardiovascular risk factors such as hypertension, dyslipidemia, obesity, diabetes mellitus, and MetS promote endothelial injury due to oxidative stress [120]. This endothelial dysfunction causes an imbalance in vasoconstriction and vasodilation, as well as increased proinflammatory factors and ROS. Oxidative stress, inflammation, and the reninangiotensin system (RAS) contribute to the development of hypertension [118]. The use of açaí seed extract can exhibit antihypertensive effects in mice fed a high-fat diet, as shown by Santos et al. [164][165][166]. In this study, animals were treated with açaí seed extract (300 mg/kg per day) and enalapril, a common antihypertensive drug. Açaí treatment increased insulin receptor expression, prevented dyslipidemia, and decreased renin and angiotensin II type 1 receptor (AT1 receptor) expression, the latter of which was linked to reduced renin and angiotensin II plasma levels. RAS downregulation in adipose tissue, related to the observed reduction in inflammation and oxidative stress, can contribute to the prevention of hypertension and obesity-related disorders [118]. Moreover, Cordeiro et al. [125] found that açaí seed extract can improve vascular dysfunction and oxidative stress related to hypertension in spontaneously hypertensive animals. The authors observed upregulation of endothelial nitric oxide synthase (eNOS) and SOD1.
ROS play an intricate role in oxidative stress and accompanying myocardial injury. Increased quantities of ROS during heart ischemia can elicit cell membrane destruction, lipid peroxidation, and dysfunction in the antioxidative defense system. For this reason, açaí has been studied as a prospective vasodilatory, anti-inflammatory, and antifibrotic agent [118]. It has been discerned that the consumption of hydroalcoholic extracts of açaí seeds can improve arterial blood pressure in rats submitted to occlusion of the left anterior descendent coronary artery (LAD) by surgery. In this study, açaí treatment prevented the progression of vascular dysfunction, cardiac hypertrophy, fibrosis, and exercise intolerance in rats with previous myocardial injury [118]. The cardioprotective and antihypertensive properties of açaí seed extract might be connected to its anti-inflammatory, antioxidant, and vasodilatory activities [91,95]. Another study performed on rats with a two-kidney, one-clip (2K-1C) renovascular hypertension model verified that the use of açaí seed extract produced antihypertensive effects and prevented endothelial dysfunction and vascular structural changes in 2K-1C hypertension. These results were attributed to interference with NOS activation and oxidative processes, as well as the inhibition of metalloproteinase-2 (MMP-2) activation [118]. Of note, the use of açaí seed extract also can produce endotheliumdependent vasodilation. Rocha et al. [95] showed that the vasodilator action of the extract is dependent on the activation of the nitric-oxide-cGMP pathway and can be involved in endothelium-derived hyperpolarizing factor release. In sum, açaí improves blood pressure through many different pathways, such as vasodilation, increased eNOS activity, and augmented production of arterial elastic fibers [95,118,149].

Cardioprotective Effects
CVDs are currently the leading cause of morbidity and mortality among adults. Although scientific progress has identified a spectrum of different risk factors for cardiovascular pathologies, the current state of prevention, and even treatment, of CVDs is suboptimal [167][168][169]. Over the last few decades, the number of deaths and disability from CVDs has continued to increase, indicating the demand for alternative treatment options for the management and prevention of CVDs. For this reason, açaí has been investigated as a prospective cardiovascular therapeutic agent due to its various cardioprotective bioactive compounds.
Figueiredo et al. [6] treated male Wistar rats with açaí pulp rich in gallic acid and total anthocyanins to evaluate the effects of açaí on animal models of cardiac remodeling. The results revealed that supplementation with açaí pulp significantly attenuated cardiac remodeling after myocardial infarction. Studies conducted by Vilhena et al. [120] and Lavorato et al. [121] described similar findings. However, restoration of normal cardiac function in remodeled mice hearts, as well as improvements in endothelial and kidney functions, inflammation, and oxidative stimuli, were also observed subsequent to açaí treatment.
Pontes et al. [122] demonstrated that the treatment of male Wistar rats with intravenous aqueous açaí pulp extract intravenously resulted in acutely elevated levels of blood flow. Mathias et al. [123] also found that supplementation with açaí pulp reduced left ventricular dysfunction, oxidative stress, changes in the myocardium metabolism, and metalloproteinases activation in rat models of cardiac remodeling. Similarly, Zapta-Sudo et al. [124] revealed that the use of hydroalcoholic açaí seed extract prevented the development of exercise intolerance, cardiac fibrosis, cardiac dysfunction, and cardiac hypertrophy in male Wistar rats. Cordeiro et al. [125] showed that açaí seed extract could also prevent other vascular dysfunctions, such as vascular remodeling, decreased elastic fibers, altered media/lumen ratio, hypertension, and oxidative damage. Figure 11 illustrates the potential cardioprotective effects of açaí.

Renoprotective Effects
Chronic kidney disease (CKD) is a general term for a group of heterogenous disorders that affect kidney structure and function. Over time, considerable research has been conducted to properly define, classify, and treat CKD. Ultimately, data has indicated that prevention is the most effective way to avoid the development and progression of renal disorders [169,170]. Because many patients with CKD present with pathology related to effects of oxidative stress and inflammation, açaí has emerged as a possible nutritional therapeutic strategy for the prevention and management of CKD.
da Costa et al. [126] found that supplementing the diets of male Wistar rats with hydroalcoholic lyophilized açaí seed extract significantly reduced renal injury and prevented renal dysfunction. da Silva et al. [127] noted that açaí seed extract decreased renal injury, prevented renal dysfunction, and thus exerted renoprotective effects, in a rat

Renoprotective Effects
Chronic kidney disease (CKD) is a general term for a group of heterogenous disorders that affect kidney structure and function. Over time, considerable research has been conducted to properly define, classify, and treat CKD. Ultimately, data has indicated that prevention is the most effective way to avoid the development and progression of renal disorders [169,170]. Because many patients with CKD present with pathology related to effects of oxidative stress and inflammation, açaí has emerged as a possible nutritional therapeutic strategy for the prevention and management of CKD.
da Costa et al. [126] found that supplementing the diets of male Wistar rats with hydroalcoholic lyophilized açaí seed extract significantly reduced renal injury and prevented renal dysfunction. da Silva et al. [127] noted that açaí seed extract decreased renal injury, prevented renal dysfunction, and thus exerted renoprotective effects, in a rat model of kidney disease via anti-inflammatory and antioxidative actions. A study conducted by Unis [128] described similar results. Moreover, El Morsy et al. [129] showed that the treatment of male Wistar albino rats with aqueous açaí fruit extract caused dose-dependent attenuation of bilateral renal ischemia/reperfusion-induced renal injury.

Antineoplastic Activity
Over time, the global frequency of cancer, a group of diseases characterized by abnormal cell growth, has continued to increase. Therefore, cancer prevention has become a topic of paramount importance within the scientific field. The chemopreventive and anticarcinogenic potency of açaí has been linked to its ability to decrease the viability of cancer cells, as well as reduce the incidence of tumors and tumor cell proliferation [76,130,153,[171][172][173]. In a study performed by Silva et al. [80], the antitumor effects of hydroalcoholic extracts from açaí bark, seed, and fruit was evaluated in vitro using cell lines derived from colorectal and breast adenocarcinomas (human Caco-2 and HT-29 colon adenocarcinoma cells and human MDA-MB-468 and MCF-7 mammary adenocarcinoma cells, respectfully). Results showed that the three extracts from various parts of the açaí plant significantly decreased cancer cell viability by increasing the presence and function of autophagic vacuoles. It was noted that all açaí extracts possessed significant polyphenol content. In another in vitro study, Silva et al. [172] assessed the cytotoxic effects of the extracts of açaí seed, pulp, and fruit in MCF-7 breast cancer cell lines. Açaí seed extract not only reduced the viability of cancer cells via ROS production, but also demonstrated cytotoxic effects and prevented the formation of new cancerous colonies. Moreover, Martinez et al. [174] studied A549 lung carcinoma cell lines treated with açaí seed extract and ascertained that the extract incited cell cycle arrest and increased apoptosis among cancer cells. Although the study lacked a comprehensive evaluation of proapoptotic pathways, the use of açaí extract was found to increase the percentage of cells in G0/G1 cycle phases and contributed to higher numbers of apoptotic cells in comparison to the untreated cells. These results revealed the potent antioxidant activity of açaí seed extract and its protective effects against cancer.
Sibuyi et al. [77] investigated the anticancer properties of gold nanoparticles (AuNPs) synthesis through the use of açaí berry on prostate (PC-3) and pancreatic (Panc-1) cancer cells. The cells were treated with açaí berry extract at concentrations of 50-200 mg/mL, which demonstrated dose-dependent cytotoxicity on the PC-3 cells. Concentrations of açaí berry extract dissolved in various solvents, starting at 50 mg/mL for those of distilled water and those of 10% cyclohexane and at 200 mg/mL those of 50% chloroform, decreased PC-3 cell viability. Açaí berry extract dissolved in 50% ethanol, no matter the concentration, did not produce any effect on PC-3 cells.
Furthermore, Monge-Fuentes et al. [78] studied murine B16F10 melanoma cell lines and found that kinetically stable açaí oil could effectively cause death of 85% of existing melanoma cells via apoptosis. Freitas et al. [79] evaluated the anticancer effects of açaí seed hexane, chloroform, and ethyl acetate extract fractions and discovered that the ethyl acetate fraction was the most effective agent in the reduction of MCF-7 breast adenocarcinomaderived cell viability through the mechanism of necroptosis. Dias et al. [81] studied malignant colon cancer HT-29 and SW-480 cells treated with polyphenolic açaí juice. Subsequent analyses revealed the ability of açaí to inhibit the growth of malignant cells without causing cytotoxic effects against the normal cells. In a similar fashion, Pacheco-Palencia et al. [82] demonstrated the effects of anthocyanin fractions in açaí fruit in the inhibition of colon HT-29 cancer cell proliferation. Choi et al. [132] demonstrated that dietary supplementation with açaí pulp provides protection against azoxymethane/dextran sulfate sodium-induced colorectal cancer in male ICR mice. Additionally, Hogan et al. [83] treated rat C-6 brain glioma cells and human MDA-468 breast cancer cells with an anthocyanin-rich extract from açaí. Although açaí extract greatly inhibited the proliferation of rat C-6 brain glioma cells, human MDA-468 breast cancer cells did not exhibit a significant response to açaí treatment. Nonetheless, Del Pozo-Insfran et al. [85] treated human HL-60 leukemia cells with açaí pulp extracts and found that the polyphenolic fractions present within the extracts played a crucial role in the reduction of leukemia cell proliferation from 56 to 86% and also increased cancer cell apoptosis.
Fragoso et al. [76] evaluated the antitumor effect of supplementation with the lyophilized pulp of açaí using a model of carcinogenesis associated with colitis in male Wistar rats. This study concluded that lyophilized açaí pulp decreased the proliferation of tumor cells and incidence of tumors with high-grade dysplasia and increased the gene expression of negative regulators of cell proliferation. Upon inspection of the açaí pulp constituents, researchers identified the presence of anthocyanins (e.g., cyanidin 3-O-glucoside, cyanidin 3-rutinoside) and carotenoids, especially β-carotene and lutein. Hence, lyophilized açaí pulp was found to have the potential to exert antitumor activity. Additionally, Fragoso et al. [131] demonstrated the anticancer effects of açaí pulp powder through its inhibition of chemically induced carcinogenesis in the colons of Wistar rats. Similarly, Romualdo et al. [133] studied the implications of spray-dried açaí pulp in chemically induced mouse colon carcinogenesis and found that it displayed antineoplastic actions. Monge-Fuentes et al. [78] studied C57BL/6 female mice and assessed the effects of kinetically stable açaí oil nanoemulsion against melanoma tumors, discovering that açaí significantly decreased their volumes. In their study on urinary bladder cells in male Swiss mice, Fragoso et al. [175] found that açaí fruit intake could prevent carcinogenesis via the reduction of DNA damage, tumor cell proliferation, and p63 expression. Comparatively, Lee et al. [176] concluded that açaí berry extract did not effectively prohibit gastric carcinogenesis induced by chronic infections of Helicobacter felis in mice.
Stoner et al. [134] investigated the effects of dietary açaí flakes (5%) in rats treated with the carcinogen N-nitrosomethylbenzylamine for 5 weeks. Açaí treatment was found to induce augmented serum antioxidant capacity through the reduction of levels of IL-5 and GRO/KC (the rat homologue for human IL-8) in the blood. The authors concluded that the proanthocyanidins and anthocyanins were responsible, at least in part, for the chemopreventive activity of açaí. Perini et al. [26] discussed the anticancer potential of various açaí extracts. These authors determined that the anticancer effects of açaí could be described by a variety of anti-inflammatory, antiproliferative, and proapoptotic effects. The anti-inflammatory actions of açaí protected animal models of cancer against tumor progression and cancer-related inflammatory consequences via the upregulation of IFN-γ and the downregulation of many proinflammatory cytokines and enzymes, such as IL-5, IL-8, TNF-α, IL-1β, myeloperoxidase (MPO), and IL-6. The antiproliferative actions of açaí, such as the downregulation of proliferating cell nuclear antigen (PCNA), p63, and Ki-67, have been shown to decrease the persistence, proliferation, and metastasis of different cancerous tumors. The proapoptotic effects of açaí berry extract, including the upregulation of caspase-3 and the downregulation of Bcl-2, may significantly decrease cancer cell viability and, therefore, tumor progression. Overall, many authors agree that the anticancer potential of açaí is derived mainly from its polyphenolic contents, especially anthocyanins [177]. These anthocyanins are warranted for use as potent antiangiogenic bioactive compounds against angiogenesis-dependent diseases, such as cancer. Figure 12 shows various cellular and molecular mechanisms of the anticancer effects of açaí.

Clinical Studies on Açaí and Human Health
In addition to preclinical studies, numerous clinical trials have evaluated the effect of açaí on different aspects of human health. These studies are summarized in Table 3. The descriptive biases presented by various clinical trials are summarized in Table 4.

Clinical Studies on Açaí and Human Health
In addition to preclinical studies, numerous clinical trials have evaluated the effect of açaí on different aspects of human health. These studies are summarized in Table 3. The descriptive biases presented by various clinical trials are summarized in Table 4. Consumption of an açaí-based smoothie (694 mg total phenolics) or a macronutrient-matched control smoothie with a high-fat breakfast meal modification Improvement of vascular function (increases in flow-mediated dilatation compared to control (p = 0.001).
A significant reduction of iAUC for total peroxide oxidative status after açaí intake. No significant modifications for heart rate, blood pressure, or postprandial glycemia Patients did not report AE [179] Simple-blinded randomized intervention trial with fourteen male athletes (mean age of 26 y) in Brazil Performance of 3 tests: 45 a ramp-incremental maximal test and two maximal bouts in two conditions (açaí or control) at 90% VO 2 max. After the first exercise bout, subjects drank 300 mL of freeze-dried and were instructed to intake the fruit 3 consecutive days, 1 h before the exercise bout to exhaustion Increase in time to exhaustion during short-term high-intensity (p = 0.045), attenuating the metabolic stress induced by exercise Not reported by the authors [180] Randomized, double-blind, placebo-controlled crossover study with 20 participants (13♀, 7♂; 22.4 ± 2.50 y) in the USA Phase 1: subjects received two capsules (500 mg of açaí or placebo). After a 7-day wash-out, subjects returned for phase 2 and consumed the opposing treatment After the first dose, no significant differences for ECG between groups, and no differences were seen for the primary or secondary hemodynamic endpoints (except for significant lower systolic blood pressure at 6 h with açaí) Patients did not report AE [181] Auditory disorder Randomized, double-blind study with 30 patients (14♀, 16♂; mean age of 50.5 y); complaint of tinnitus, hearing thresholds; annoyance score of at least four in Brazil Patients were divided into a placebo (starch capsules) and a treated group that received an extract of dry açaí (100 mg/capsule) Reduction in the discomfort of tinnitus evaluated by THI (p = 0.006); significant improvement for anxiety disorders symptoms (p = 0.016). No significant differences for oxidative metabolism biomarkers, but a decrease in posttreatment values for all groups Patients did not report AE [31]   In addition, Kim et al. [182] evaluated the anti-inflammatory effect of açaí supplementation in patients diagnosed with MetS through a twelve-week randomized, double-blind, placebo-controlled clinical trial. However, the daily intake of 325 mL of an açaí-beverage (with 1139 mg/L of gallic acid) did not modify biomarkers for lipid and glucose metabolism in the study participants. Even so, açaí pulp juice significantly decreased IFN-γ levels in patients receiving the dietary açaí supplement. One limitation of this trial was the small number of included subjects and the lack of investigation of adverse outcomes among patients.
In overweight subjects, Udani et al. [183] revealed that the consistent intake of 100 g açaí pulp, twice a day for one month, reduced fasting glucose and insulin levels. Compared to baseline, the consumption of açaí improved the postprandial increase in glycemia following a standardized meal. These results also indicated that the consumption of 100 g of açaí pulp by overweight subjects engenders significant reductions in both total cholesterol and LDL levels.

Effect on Prostate Cancer
Further, Kesller et al. [184] investigated the effects of a mixture of tea and açaí juice in patients with prostate cancer and observed a possible stabilization of prostate-specific antigen (PSA). Because the preparation of the dietary supplement used in this study involved many different components, a limitation of this study is the lack of ability to pinpoint the exact causative factor for the observed results.

Toxicity and Safety Studies
On the whole, current scientific literature is deficient in information regarding the toxicity of açaí. Marques et al. [18] published the first cytotoxic, genotoxic, and antigenotoxic assessment of açaí fruit oil in human cell cultures. These authors showed that the acute treatments of EOO (2.5, 10, 100, 500, and 1000 µg/mL) demonstrated neither cytotoxic effects nor DNA damage in HepG2 and human lymphocytes. Moreover, samples from mammalian leukocytes did not suffer any genotoxic effects following the administration of 1% of açaí oil at doses of 30, 100, and 300 mg/kg for 14 days.
Additionally, Ribeiro et al. [185] tested acute and subacute doses of açaí pulp in mice at 3.33, 10.0, and 16.67 g/kg and demonstrated that no genotoxic effects were induced by the açaí administration. To further illustrate this point, another study suggested the absence of toxic effects caused by açaí at acute doses up to 2000 mg/kg in animals (such as mice), which could be equated to the human consumption of 140 g of açaí at one time [10].
However, Marques et al. [186] used rat models to demonstrate that the oral administration of açaí oil at doses of 30, 100, and 300 mg/kg over a time period of 14 days resulted in altered thyroid cell follicular morphology and reduced size of follicular cells due to hypertrophy and unorganized growth. Interestingly, these doses of açaí oil also caused hepatocyte vacuolization, as well as a shift from eosinophilic to basophilic characteristics in the cells.
Moreover, Caiado et al. [187] explored the toxic effects of açaí fruit-based dye in the retina of rabbits. The results of this study revealed no potential toxicity at 10% and 25% concentrations of açaí dye. However, at a concentration of 35%, the açaí fruit-based dye induced ganglion cell edema 24 h after administration, as well as nerve bundle damage, multilamellar bodies, and vacuolization, in the retinal inner nuclear layers. While it can be seen that açaí is ordinarily safe, more data are needed in order to come to conclusively determine the toxicity of açaí.

Economic Importance
Açaí has enormous economic potential in many fields of industry. In the food industry, açaí may be used in the production many goods, ranging from probiotic beverages to desserts to ice cream. Due to its potent effects in preventing morphological changes in principally Lactobacillus rhamnosus, the fruit can be easily used as a suitable matrix for products that use this microorganism as a probiotic agent [188][189][190]. Additionally, açaí is an excellent alternative source of natural pigment for yogurts [191]. Of note, isotonic beverages were also developed based on the biological properties of açaí. Data have indicated a wider range of health benefits and antioxidant capacity in food formulations incorporating açaí than those of traditional commercialized isotonic drinks [192].
Moreover, in the cosmetic industry, açaí has been used to create multicomplex emulsions that enhance the photoprotective effects of sunscreens formulas. Due to its antioxidant capacity, açaí also has potential as an ingredient in various other skincare products, such as skin lotions [144,193,194]. Açaí has also been utilized as a stimulatory ingredient to enhance skin microcirculation in rat models [195]. Recently, Xiao et al. [196] developed and evaluated a new thermoreversible gel formulated with açaí extract. This study validated the implication of açaí extract in the treatment keratoconus through the use of a rabbit model, in which satisfactory therapeutic results were demonstrated.
In the biotechnological industry, açaí-derived ultrafine fibers have been used to compose innovative pH sensors for the visual monitoring of food quality [197]. Additionally, because açaí-derived biomass has been found to be capable of absorption of Cd (II), Pb (II), and Cr (III), it has been put to use in Brazil for the remediation of water pollution [198]. The residual biomass of açaí has also been processed and assessed for potential in energy production due to its physicochemical profile. Although açaí-derived energy is not highly generated yet, it is a prospective green alternative to the traditional globalized energy sources, such as the petroleum and the mineral coal [11]. All in all, it can be seen that there are multitudinous industrial purposes for açaí.

Conclusions, Limitations, and Future Perspectives
Our results show that açaí has medicinal properties and the economic potential for widespread use throughout the food and cosmetic industry. The fruit presents a rich phytochemical profile composed of phenolic compounds, quinones, terpenes, and norisoprenoids, all of which are related to its health-promoting and disease-preventing potential. In vitro and in vitro studies demonstrated that açaí possesses antioxidant and anti-inflammatory effects; exerts cardioprotective, gastroprotective, hepatoprotective, neuroprotective, and renoprotective activities; improves hyperinsulinemia and dyslipidemia; and shows antineoplastic actions. Additionally, açaí exerts antimicrobial and antiparasitic effects. Clinical trials have demonstrated that açaí protects against prostate cancer, MetS risk factors, and auditory dysfunctions. Moreover, its derivatives, such as berry extracts, whole fruit extracts, seed extracts, and phytochemically enriched extracts, have no hepatotoxicity, cardiotoxicity, or nephrotoxicity, strengthening its safety and health potential. However, our work had some limitations. Firstly, numerous included studies did not specifically define the composition of the utilized açaí. Secondly, a limited number of clinical studies have been conducted on this fruit, especially concerning direct human consumption. In addition, the studies included in this paper are heterogeneous due to the variety of forms of açaí administration used (e.g., capsules, smoothie, juice, extract, mixture with other components) and in different doses. In short, the accumulated scientific evidence on the properties of açaí, in the absence of undesirable effects, awards this plant a promising future in health promotion and disease prevention. Moreover, there is a vast economic potential of açaí in the pharmaceutical, food, and cosmetic industries.